1. Field of the Invention
This invention lies in the field of fluid therapy in humans, and more particularly in the field of aqueous solutions for parenteral, oral, dialysis, and irrigation therapy which employ at least one of l-lactate anions, pyruvate anions, d-betahydroxybutyrate anions, acetoacetate anions, or mixtures thereof in combination with selected cations.
2. Prior Art
Previously, I have provided improved electrolyte solutions for in vivo and in vitro usage which contain l-lactate and pyruvate anions, and/or d-betahydroxybutyrate and acetoacetate anions in respective defined ratios in combination with defined Na:Cl ratios; see my copending U.S. patent applications Ser. Nos. 748,232 and 747,792, both filed Jun. 24, 1985, and also my copending U.S. patent application Ser. Nos. 747,858 and 748,184, also filed on such date. However, it is now appreciated that the benefits of using l-lactate, pyruvate, d-betahydroxybutyrate, and/or acetoacetate anions need not be restricted by these previously taught relationships of anion pair ratios to Na:Cl ratios.
The prior art indicated in the xe2x80x9cBackgroundxe2x80x9d sections of these earlier patent applications is incorporated by reference into the present application.
Previously, only racemic mixtures of lactate anions containing both d- and l-forms of lactate have been used in aqueous solutions for human parenteral therapy. The other major organic anion used in human parenteral fluids has been acetate. So far as is now known, the natural l-form of lactate anion has heretofore never been used, apart from the unnatural d-form, in human fluid therapy.
Sodium lactate solutions, used in pharmaceutical practices, are not specified in terms of isomeric structure. In the U.S. and British Pharmacopeias, lactate is defined and approval was duly granted for use of the d,l-lactate mixture. Hence, the d,l-lactate is the form used in contemporary pharmaceutical practice. The l-lactate is recognized to be the physiologically predominant form which is metabolized by different pathways and with different effects than is the d-lactate.
The toxicity of d-lactate has been described in humans (see Oh M S et al N Eng J Med 301: 249-251, 1979; Perlmutter, D H et al J Pediatrics 102: 234-238, 1983; Stolberg, L et al N Eng J Med 306: 1344-1348, 1982). Thus, the d-form has now been discovered to cause adverse and toxic effects when administered to mammals. For example, when an aqueous 20 mM/l d-lactate (or d-lactic acid) is administered parenterally to a rat, swelling of brain tissue is observed because the brain takes in the slowly metabolized d-lactatexe2x88x92 plus an equivalent amount of K+. With continued administration, coma develops, the cerebral edema worsens and death ensues. In contrast, when l-lactate is similarly administered, the differential concentration of l-lactate between intracellular and extracellular fluid does not cause coma or death. For another example, Veech et al. (Veech, R L and Fowler, R C., xe2x80x9cCerebral Dysfunction and Respiratory Alkalosis During Peritoneal Dialysis with d-Lactate Containing Peritoneal Dialysis Fluidsxe2x80x9d, Am. J. Med., 1987 (in press)) points out that the severe recurrent metabolic alkelemia described by Kenamond et al. (xe2x80x9cSevere Recurrent Alkalemia in a Patient Undergoing Continuous Cyclic Peritoneal Dialysisxe2x80x9d, Am. J. Med., 548-550, 1986) was secondary to an encephalopathy caused by the inclusion of d,l-lactate in routine dialysis fluids. Because of such encephalopathological results, parenteral solutions containing the racemic d,l-lactate anions should not be administered for therapeutic purposes.
All previous commercial formulations of fluids for human therapy use lactate or lactic acid in the racemic d,l form as defined in the United States or British Pharmacopeia (see the United States Pharmacopeia 21st edition, January 1985, p 581, 945-946, 1186; United States Pharmacopeia Convention, Rockville, and British Pharmacopeia 1980, p 250, 666, 667, Her Majesty""s Stationary Office, London). Sodium d,l-lactate solutions are currently and conventionally used for three major purposes in current medical practice. First, sodium d,l-lactate solution is used parenterally as an alkalinizing agent to correct acidosis. Secondly, it is used in parenteral fluid therapy to normalize the Na:Cl ratio from the 1:1 ratio found in normal saline. Thirdly, it is used as the counter ion in peritoneal dialysis solutions. In addition, it could also be used in current hemodialysis to replace the acetate anion, or, in its H+ form, as an acid to be added to a bicarbonate hemodialysis fluid.
Prior to the teachings contained in my afore referenced U.S. Ser. No. 748,232, pyruvate anions d-betahydroxybutyrate anions, and acetoacetate anions in aqueous solution, so far as is now known, were never used in human therapeutic fluids.
This invention relates to a process for accomplishing fluid therapy without encephalopathy or metabolic bone disease and other complications resulting from use of present fluid formulations in a living human involving the introduction into the body of such human an aqueous solution containing at least one permeant monoanionic metabolite selected from the group consisting of l-lactate anions, pyruvate anions, d-betahydroxybutyrate  D-xcex2-hydroxybutyrate anions, acetoacetate anions, or mixtures of such anions.
Here, l-lactate is defined as that form of lactate anion found in mammalian tissues and designated l or L-lactate. It is identified by its ability to react with NAD+ to form pyruvate in a reaction catalyzed by mammalian lactate dehydrogenase (EC 1.1.1.27). The form of l-lactate which is dextrorotatory in aqueous solution is designated l-(+) while the salts of l-lactate which in aqueous solution are levorotatory are designated l-(xe2x88x92)lactate (see US Dispensatory, Osol, A, Pratt, R, Gennar, A R, eds. p 658. J R Lippcott. Philadelphia, 1973). Pyruvate and acetoacetate have no sterospecificity.
More particularly, this invention is directed to improved methods and optionally stable fluids for conventional administration to humans such as, (a) oral ingestion of an aqueous solution containing at least one of such anions, or a mixture of such anions, (b) parenteral therapy involving, for example, the intravenous administration of an aqueous solution containing at least one of such anions, or a mixture thereof, (c) dialysis therapy (hemo or peritoneal) using aqueous solutions containing at least one of such anions, (d) dialysis therapy (hemo or peritoneal) where acetic acid is replaced with at least one acid of the group consisting of l-lactate, pyruvate, d-beta  D-xcex2-hydroxybutyrate or acetoacetic acid, preferably l-lactate, and/or (e) irrigation therapy.
One presently preferred such anion comprises l-lactate. Thus, surprisingly, encephalopathy, metabolic bone disease, and many other complications are not only completely avoided by using l-lactate (or one of the other metabolite anions herein identified and used in the practice of this invention) in place of racemic d-l-lactate, but also the substitution of, for example, l-lactate for d-l-lactate, in solutions employed in fluid therapy, does not cause any change in the heretofore known beneficial physiological or pharmacological effectiveness of such fluids.
In general, a solution containing at least one such anion is administerable for generally the same purposes that prior art parenteral fluids or dialysis fluids are used which contain racemic d-l-lactate anions. For examples, such a solution can be used to treat acidosis, dehydration, blood electrolyte depletion, shock, malnutrition, uremia and the like.
Because mixtures of l-lactate anions and pyruvate anions, and mixtures of d-beta  D-xcex2-hydroxybutyrate anions and acetoacetate anions, in solutions each constitute near-equilibrium couples, which can vary widely in concentration under normal physiological conditions, as explained, for example, in my aforereferenced U.S. patent application Ser. No. 748,232, these anions can be employed with little or no adverse side effects in parenteral fluids and the like. Moreover, the therapeutic use of these anion couples (a) tends to maintain a normal plasma milliequivalent ratio of sodium cations to chloride anions, (b) thus tends to prevent hyperchloremic acidosis, and (c) accomplishes electrolyte and fluid and resuscitation therapy. The anions taught by this invention permit one to avoid the known untoward effects of high levels of the d-lactate anion (see Veech, R L, Fowler, R C, op. cited above) or of acetate anions which are now the major organic anions conventionally added to parenteral fluids (See Veech R L. The toxic impact of parenteral solutions on the metabolism of cells: a hypothesis for physiological parenteral therapy. Am J Clin Nutr 44: 519-551, 1986).
Other and further objects, aims, purposes, features, advantages, embodiments, applications, and the like will be apparent to those skilled in the art from the teachings of the present specification taken together with the claims.